Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Volume 37 , Issue 5
Showing 1-23 articles out of 23 articles from the selected issue
Review
  • Kiyoko Kaneko, Yasuo Aoyagi, Tomoko Fukuuchi, Katsunori Inazawa, Norik ...
    2014 Volume 37 Issue 5 Pages 709-721
    Published: May 01, 2014
    Released: May 01, 2014
    [Advance publication] Released: February 20, 2014
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    Purines are natural substances found in all of the body’s cells and in virtually all foods. In humans, purines are metabolized to uric acid, which serves as an antioxidant and helps to prevent damage caused by active oxygen species. A continuous supply of uric acid is important for protecting human blood vessels. However, frequent and high intake of purine-rich foods reportedly enhances serum uric acid levels, which results in gout and could be a risk factor for cardiovascular disease, kidney disease, and metabolic syndrome. In Japan, the daily intake of dietary purines is recommended to be less than 400 mg to prevent gout and hyperuricemia. We have established an HPLC method for purine analysis and determined purines in a total of 270 foodstuffs. A relatively small number of foods contained concentrated amounts of purines. For the most part, purine-rich foods are also energy-rich foods, and include animal meats, fish meats, organs such as the liver and fish milt, and yeast. When the ratio of the four purine bases (adenine, guanine, hypoxanthine, and xanthine) was compared, two groups of foods were identified: one that contained mainly adenine and guanine and one that contained mainly hypoxanthine. For patients with gout and hyperuricemia, the amount of total purines and the types of purines consumed, particularly hypoxanthine, are important considerations. In this context, the data from our analysis provide a purine content reference, and thereby clinicians and patients could utilize that reference in nutritional therapy for gout and hyperuricemia.
Regular Articles
  • Ligia Carolina da Silva Prado, Denise Brentan Silva, Grasielle Lopes d ...
    2014 Volume 37 Issue 5 Pages 722-730
    Published: May 01, 2014
    Released: May 01, 2014
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    We applied a taxonomic approach to select the Eugenia dysenterica (Myrtaceae) leaf extract, known in Brazil as “cagaita,” and evaluated its gastroprotective effect. The ability of the extract or carbenoxolone to protect the gastric mucosa from ethanol/HCl-induced lesions was evaluated in mice. The contributions of nitric oxide (NO), endogenous sulfhydryl (SH) groups and alterations in HCl production to the extract’s gastroprotective effect were investigated. We also determined the antioxidant activity of the extract and the possible contribution of tannins to the cytoprotective effect. The extract and carbenoxolone protected the gastric mucosa from ethanol/HCl-induced ulcers, and the former also decreased HCl production. The blockage of SH groups but not the inhibition of NO synthesis abolished the gastroprotective action of the extract. Tannins are present in the extract, which was analyzed by matrix assisted laser desorption/ionization (MALDI); the tannins identified by fragmentation pattern (MS/MS) were condensed type-B, coupled up to eleven flavan-3-ol units and were predominantly procyanidin and prodelphinidin units. Partial removal of tannins from the extract abolished the cytoprotective actions of the extract. The extract exhibits free-radical-scavenging activity in vitro, and the extract/FeCl3 sequence stained gastric surface epithelial cells dark-gray. Therefore, E. dysenterica leaf extract has gastroprotective effects that appear to be linked to the inhibition of HCl production, the antioxidant activity and the endogenous SH-containing compounds. These pleiotropic actions appear to be dependent on the condensed tannins contained in the extract, which bind to mucins in the gastric mucosa forming a protective coating against damaging agents. Our study highlights the biopharmaceutical potential of E. dysenterica.
  • Tatsuya Muto, Haruki Usuda, Aya Yamamura, Koji Yoshida, Ai Ohashi, Kum ...
    2014 Volume 37 Issue 5 Pages 731-739
    Published: May 01, 2014
    Released: May 01, 2014
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    Serotonin (5-hydroxytryptamine; 5-HT) is known to be activated during ischemia–reperfusion and triggers contractile dysfunction and pathological apoptosis. Here, the beneficial effects of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine was demonstrated on ischemia–reperfusion injury in guinea-pig hearts perfused using the Langendorff technique. The recovery (%) of left ventricular developed pressure (LVDP) by fluvoxamine (5×10−8 M) was 95.4% (control: 32%), which was consistent with the inhibition of mitochondrial Ca2+([Ca2+]m) uptake induced by changes in the Ca2+ content and acidification of the perfusate, and similar to reperfusion following global ischemia in Langendorff-perfused hearts. Fluvoxamine inhibited the increase in [Ca2+]m induced by changes in the Ca2+ content of the perfusate in perfused preparations of mitochondria, which was similar to the results obtained with the mitochondrial permeability transition pore (MPTP) opener atractyroside. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive cells were significantly less in fluvoxamine-treated hearts than in control hearts, with decreases in caspase-3 activity. These results suggest that SSRI inhibits opening of the MPTP by preventing [Ca2+]m overload-induced apoptosis related to the endogenous accumulation of 5-HT in ischemia–reperfusion hearts.
  • Mengshu Wang, Yong Zhang, Bingxue Sun, Yanan Sun, Xin Gong, Yongge Wu, ...
    2014 Volume 37 Issue 5 Pages 740-747
    Published: May 01, 2014
    Released: May 01, 2014
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    The purpose of this study was to investigate the permeability of exendin-4-loaded chitosan nanoparticles using the Madin Darby canine kidney (MDCK) cell monolayer as an in vitro model and the rat intestine as an ex vivo model of the human intestinal barrier. A series of formulations of sodium tripolyphosphate (TPP) and chitosan with different molecular weights and degrees of deacetylation was evaluated. The formulation consisting of 0.1% TPP and 0.2% chitosan (400 kDa, 95% degree of deacetylation), which gave optimized monodispersed particle size (303.1±10.36 nm), zeta potential (18.37±1.15 mV) and encapsulation efficiency (38.0±2.6%), was used for further analysis. After determining their biocompatibility, the transport potential of drug-loaded chitosan nanoparticles was evaluated and compared with free exendin-4 using both MDCK cell monolayers and different rat intestinal segments. Mechanisms underlying enhanced transport of exendin-4 in the cell model were also explored. Compared with free exendin-4, the absorption of optimized chitosan nanoparticles was enhanced by 4.7-fold in MDCK cell monolayers and by 2.0–2.78-fold in different rat intestinal segments, with no significant difference between the duodenum, jejunum and ileum. As supported by confocal laser scanning microscopic analysis, the lower enhancement of absorption in the intestine compared to the cell monolayer likely resulted from the chitosan nanoparticle-mediated opening of cellular tight junctions and not through intracellular transport. These findings suggest that the potential application of chitosan nanoparticles as delivery carriers of exendin-4 is limited and may need further modifications.
  • Hiroko Ushikubo, Yui Tanimoto, Kazuho Abe, Tomohiro Asakawa, Toshiyuki ...
    2014 Volume 37 Issue 5 Pages 748-754
    Published: May 01, 2014
    Released: May 01, 2014
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    Amyloid β protein (Aβ) self-assembles into insoluble fibrils, and forms the senile plaques associated with Alzheimer’s disease. 3,3′,4′,5′-Tetrahydroxyflavone, a synthetic analogue of the natural flavonoid fisetin, has been found to potently inhibit Aβ fibril formation. In the present study, we investigated how inhibition of Aβ fibril formation by this flavonoid affects Aβ conformation and neurotoxicity. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of Aβ1-42 (20 µM) incubated with or without 3,3′,4′,5′-tetrahydroxyflavone demonstrated that 3,3′,4′,5′-tetrahydroxyflavone (100 µM) rapidly caused formation of atypical Aβ conformers, which appeared as a very broad, smear-like band in the high molecular weight region and were distinguishable from soluble Aβ oligomers or mature Aβ fibrils. Transmission electron microscopy (TEM) revealed that large spherical Aβ aggregates were preferentially formed in the presence of 3,3′,4′,5′-tetrahydroxyflavone. The SDS-resistant, smear-like band on SDS-PAGE and the large spherical aggregates in TEM both disappeared after heat treatment (100°C, 10 min). Furthermore, a neurotoxicity assay with cultured rat hippocampal neurons demonstrated that Aβ incubated with 3,3′,4′,5′-tetrahydroxyflavone was significantly less toxic than Aβ incubated without the flavonoid. These results suggest that the newly synthesized fisetin analogue 3,3′,4′,5′-tetrahydroxyflavone directly produces atypical, large Aβ aggregates and reduces Aβ toxicity.
  • Heon-Sub Shin, Sang-Yong Park, Eun-Son Hwang, Don-Gil Lee, Gafurjon Tu ...
    2014 Volume 37 Issue 5 Pages 755-763
    Published: May 01, 2014
    Released: May 01, 2014
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    This study was conducted to test whether ginsenoside F2 can reduce hair loss by influencing sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and the transforming growth factor beta (TGF-β) pathway of apoptosis in dihydrotestosterone (DHT)-treated hair cells and in a DHT-induced hair loss model in mice. Results for ginsenoside F2 were compared with finasteride. DHT inhibits proliferation of hair cells and induces androgenetic alopecia and was shown to activate an apoptosis signal pathway both in vitro and in vivo. The cell-based 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the proliferation rates of DHT-treated human hair dermal papilla cells (HHDPCs) and HaCaTs increased by 48% in the ginsenoside F2-treated group and by 12% in the finasteride-treated group. Western blot analysis showed that ginsenoside F2 decreased expression of TGF-β2 related factors involved in hair loss. The present study suggested a hair loss related pathway by changing SCAP related apoptosis pathway, which has been known to control cholesterol metabolism. SCAP, sterol regulatory element-binding protein (SREBP) and caspase-12 expression in the ginsenoside F2-treated group were decreased compared to the DHT and finasteride-treated group. C57BL/6 mice were also prepared by injection with DHT and then treated with ginsenoside F2 or finasteride. Hair growth rate, density, thickness measurements and tissue histotological analysis in these groups suggested that ginsenoside F2 suppressed hair cell apoptosis and premature entry to catagen more effectively than finasteride. Our results indicated that ginsenoside F2 decreased the expression of TGF-β2 and SCAP proteins, which have been suggested to be involved in apoptosis and entry into catagen. This study provides evidence those factors in the SCAP pathway could be targets for hair loss prevention drugs.
  • Xuxu Zheng, Lixia Guo, Daoqing Wang, Xiaohong Deng
    2014 Volume 37 Issue 5 Pages 764-770
    Published: May 01, 2014
    Released: May 01, 2014
    [Advance publication] Released: March 04, 2014
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    In the brain, Neuromedin U2 receptor (NMU2R) is prominent in the hypothalamic regions and is known to be associated with regulation of several important physiological functions, including food intake, energy balance, stress response, and nociception. In this article, by random screening of compounds using the model of high-throughput screening for NMU2R stable expression, NMU2R negative and NMU2R short hairpin RNA (shRNA) knockdown HEK293 cell lines, for the first time, we discovered that p-synephrine, which is the primary protoalkaloid in Citrus aurantium (bitter orange) and is widely used in weight loss and weight management products, is a highly potent and selective NMU2R agonist. In NMU2R activating ability experiments, p-synephrine was found binding to NMU2R with high efficacy and potency; the efficacy, 50% of the maximum possible effect (EC50) and potency values were determined to be 7.207, 6.604 and 0.227 µmol/L for the NMU2R, respectively. Our researches have important theoretical value for elucidating the mechanisms of p-synephrine in body weight and energy balance regulation. These data provide further evidence for widespread roles for p-synephrine and its receptors in the brain.
  • Nayara Santos da Silveira, Grasielle Lopes de Oliveira-Silva, Bianca d ...
    2014 Volume 37 Issue 5 Pages 771-778
    Published: May 01, 2014
    Released: May 01, 2014
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    We investigated the psychostimulant, rewarding, and anxiolytic-like effects of pulegone. Possible interactions between pulegone and menthol concerning their psychostimulant effect were also analyzed. General mouse activity after pulegone treatment, and the interacitons between pulegone and menthol, were determined in the open field. The anxiolytic-like activity, motor coordination and strength force were evaluated using the elevated plus maze (EPM), rotarod test and grasping test, respectively. The motivational properties of pulegone were evaluated by pairing the drug effects on the mice with the least preferred compartment (previously determined) of a conditioned place preference (CPP) apparatus. Pulegone increased mouse locomotor activity and immobilization time. Verapamil, but not diltiazem, haloperidol or picrotoxin, decreased the psychostimulation induced by pulegone. Pulegone also decreased grooming and rearing behaviors and caused motor incoordination and weakness at high doses. Pulegone increased the time spent by mice in the open arms of the EPM, and flumazenil pre-treatment did not alter this effect. Pulegone either produced no CPP or induced conditioned place aversion. The changes in mouse ambulatory activity caused by the association of pulegone with menthol were either lower than those predicted by the theoretical curve or not different from the predicted values. Therefore, pulegone induces a verapamil-sensitive psychostimulant effect that appears to independ on the opening of L-type calcium channels. Pulegone has negative reinforcing properties and seems to possess anxiolytic-like actions unrelated to the benzodiazepine site of the γ-aminobutyric acid type A (GABAA) receptor. Finally, pulegone might act in an addictive or synergic way with menthol.
  • Ayano Iwazaki, Kazuhiro Takahashi, Yui Tamezane, Kenta Tanaka, Minami ...
    2014 Volume 37 Issue 5 Pages 779-784
    Published: May 01, 2014
    Released: May 01, 2014
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    The interaction between angiotensin II type 1 (AT1) receptor blockers (ARBs), such as losartan potassium (LO), candesartan (CA), and telmisartan (TE), and dietary fiber was studied as to the level of free ARB in vitro. When ARB was incubated with soluble (sodium alginate, pectin, and glucomannan) or insoluble (cellulose and chitosan) dietary fiber, the levels of free LO, TE, and CA decreased. This resulted only from mixing the dietary fiber with the ARBs and differed among the types of dietary fiber, and the pH and electrolytes in the mixture. The levels of free LO and TE tended to decrease with a higher concentration of sodium chloride in pH 1.2 fluid. These results suggest that it is important to pay attention to the possible interactions between ARBs and dietary fiber.
  • Yue Zhang, Haiwen Song, Zhenhua Shang, Aibing Chen, Daowei Huang, Hua ...
    2014 Volume 37 Issue 5 Pages 785-793
    Published: May 01, 2014
    Released: May 01, 2014
    [Advance publication] Released: March 05, 2014
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    A set of polyethylene glycol (PEG)–resveratrol (RES) conjugates with amino acid as spacers was designed and synthesized to improve certain defects of resveratrol, such as poor solubility, its short half-life and the difficulty of obtaining controlled release. Amino acids, which are released along with RES, are necessary for human health and likely have a facilitating effect on the absorption of the drug. The prepared PEG conjugates were characterized by FT-IR, 1H-NMR, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Evaluation of free RES, loading capability, solubility and in vitro release of conjugates was also conducted. The results show that solubility in water of all the conjugates is over 900 mg·mL−1 and controlled release of RES was achieved. Therefore, the developed PEG conjugate is a favorable system for modifying the solubility and bioavailability of RES.
  • Jung Ok Lee, Ji Wook Moon, Soo Kyung Lee, So Mi Kim, Nami Kim, Seong-G ...
    2014 Volume 37 Issue 5 Pages 794-801
    Published: May 01, 2014
    Released: May 01, 2014
    [Advance publication] Released: February 20, 2014
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    Rhus verniciflua STOKES (RVS) is used as an anti-cancer agent in traditional herbal medicine. However, the underlying molecular mechanism of its action is poorly understood. Here, we elucidated the mechanism of the anti-cancer mechanism of RVS in MCF-7 human breast cancer cells. We found that RVS increased the phosphorylation of AMP-activated protein kinase (AMPK) and downstream acetyl-CoA carboxylase (ACC) and suppressed cell viability in an AMPK-dependent fashion. RVS also induced an increase in reactive oxygen species (ROS) levels. RVS-induced AMPK phosphorylation was not observed in the presence of N-acetyl-cysteine (NAC), which indicated that ROS is associated with RVS-induced AMPK phosphorylation. In addition, fluorescent staining (Annexin V/propidium iodide) revealed that RVS increased the expression of Annexin V, which indicates that RVS leads to cancer-induced apoptosis. Moreover, RVS increased the phosphorylation of p53 and the expression of Bax. The inhibition of AMPK blocked RVS-induced p53 phosphorylation and Bax expression, which suggests that AMPK is involved in RVS-induced cancer apoptosis. Taken together, these results demonstrate that RVS has anti-tumor effects on MCF-7 cells through an AMPK-signaling pathway.
  • Tohru Obata, Yuka Suzuki, Noriko Ogawa, Ippei Kurimoto, Hiromitsu Yama ...
    2014 Volume 37 Issue 5 Pages 802-807
    Published: May 01, 2014
    Released: May 01, 2014
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    Sapacitabine (CS-682 or CYC682; 1-[2-C-cyano-2-deoxy-β-D-arabino-pentfuranosyl]N4-palmitoyl cytosine), a novel antitumor 2′-deoxycytidine analogue, shows a marked reduction in the water solubility because of the fatty acid side chain on the N4 group of the cytosine moiety. Poor water solubility is one of the important reasons why sapacitabine does not exert maximum antitumor activity. Therefore, we attempted to improve the water solubility of sapacitabine using a novel surfactant, Soluplus®, which consisted of a polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer. In this study, we examined whether Soluplus® increased the water solubility and an antitumor activity of sapacitabine. The cytotoxicity of Soluplus® alone was lower than that of Tween 80 and Kolliphor® D-α-tocopherylpolyethylene glycol 1000 succinate (TPGS). The water solubility and the chemosensitivity of sapacitabine against several tumor cell lines to sapacitabine markedly increased upon using Soluplus®. In addition, the potential of Soluplus® including sapacitabine in increasing the antitumor activity was compared with sapacitabine alone in vivo. Although the total dose in the experimental period was considerably lower than the effective dose of sapacitabine alone, the life span of mice treated with sapacitabine containing 40 mg/mL Soluplus® increased by 150%. If Soluplus® was used as the solubilizing agent in clinical trials of sapacitabine, a low administration dose was appeared to require, and thus side effects might be prevented.
  • Nam Ah Kim, In Bok An, Dae Gon Lim, Jun Yeul Lim, Sang Yeol Lee, Woo S ...
    2014 Volume 37 Issue 5 Pages 808-816
    Published: May 01, 2014
    Released: May 01, 2014
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    The protein size, electrical interaction, and conformational stability of etanercept (marketed as Enbrel®) were examined by thermodynamic and light scattering methods with changing pH and buffer concentration. As pH of etanercept increased from pH 6.6 to 8.6, electrical repulsion in the solution increased, inducing a decrease in protein size. However, the size changed less in high buffer concentration and irreversible aggregation issues were not observed; in contrast, aggregates of about 1000 nm were observed in low buffer concentration at the pH range. Three significant unfolding transitions (Tm) were observed by differential scanning calorimetry (DSC). Unlikely to Tm1, Tm2 and Tm3 were increased as the pH increased. Higher Tm at high buffer concentration was observed, indicating increased conformational stability. The apparent activation energy of unfolding was further investigated since continuous increase of Tm2 and Tm3 was not sufficient to determine optimal conditions. A higher energy barrier was calculated at Tm2 than at Tm3. In addition, the energy barriers were the highest at pH from 7.4 to 7.8 where higher Tm1 was also observed. Therefore, the conformational stability of protein solution significantly changed with pH dependent steric repulsion of neighboring protein molecules. An optimized pH range was obtained that satisfied the stability of all three domains. Electrostatic circumstances and structural interactions resulted in irreversible aggregation at low buffer concentrations and were suppressed by increasing the concentration. Therefore, increased buffer concentration is recommended during protein formulation development, even in the earlier stages of investigation, to avoid protein instability issues.
  • Tohru Yahara, Masanori Tachikawa, Shin-ichi Akanuma, Yoshiyuki Kubo, K ...
    2014 Volume 37 Issue 5 Pages 817-825
    Published: May 01, 2014
    Released: May 01, 2014
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    Taurine transporter (TauT/SLC6A6) is an “honorary” γ-aminobutyric acid (GABA) transporter because of its low affinity for GABA. The sequence analysis of TauT implied the role of Gly57, Phe58, Leu306 and Glu406 in the substrate recognition of TauT, and amino acid-substitutions were performed. Immunocytochemistry supported no marked effect of mutations on the expression of TauT. TauT-expressing oocytes showed a reduction in [3H]taurine uptake by G57E, F58I, L306Q and E406C, and change in [3H]GABA uptake by G57E and E406C, suggesting their significant roles in the function of TauT. G57E lost the activity of [3H]taurine and [3H]GABA uptake, suggesting that Gly57 is involved in the determination of substrate pocket volume and in the interaction with substrates. E406C exhibited a decrease and an increase in the affinity for taurine and GABA, respectively, suggesting the involvement of Glu406 in the substrate specificity of TauT. The inhibition study supported the role of Glu406 in the substrate specificity since [3H]taurine and [3H]GABA uptake by E406C was less sensitive to taurine and β-alanine, and more sensitive to GABA and nipecotic acid than was the case with wild type of TauT. F58I had an increased affinity for GABA, suggesting the involvement of Phe58 in the substrate accessibility. The kinetic parameters showed the decreased and increased affinities of L306Q for taurine and GABA, respectively, supporting that substrate recognition of TauT is conformationally regulated by the branched-side chain of Leu306. In conclusion, the present results suggest that these residues play important roles in the transport function and substrate specificity of TauT.
  • Min Soo Kim, Jung Min Yu, Hee Jung Kim, Hae Bok Kim, Seung Tae Kim, Su ...
    2014 Volume 37 Issue 5 Pages 826-833
    Published: May 01, 2014
    Released: May 01, 2014
    [Advance publication] Released: March 05, 2014
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    In Alzheimer’s disease (AD), extensive neuronal loss and a deficiency of the neurotransmitter acetylcholine (ACh) are the major characteristics during pathogenesis in the brain. In the present study, we aimed to investigate whether representative ginsenosides from ginseng can regulate choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT), which are required for cholinergic neurotransmission. Our results revealed that Re and Rd induced effectively the expression of ChAT/VAChT genes in Neuro-2a cells as well as ACh elevation. Microtubule-associated protein-2 (MAP-2), nerve growth factor receptor (p75), p21, and TrkA genes and proteins were also significantly expressed. Moreover, both activated extracelullar signal-regulated protein kinase (ERK) and Akt were inhibited by K252a, a selective Trk receptor inhibitor. These findings strongly indicate that Re and Rd play an important role in neuronal differentiation and the nerve growth factor (NGF)-TrkA signaling pathway. High performance liquid chromatography analysis showed that Re and Rd administered orally were transported successfully into brain tissue and increased the level of ChAT and VAChT mRNA. The present study demonstrates that Re and Rd are selective candidates for upregulation of the expression of cholinergic markers, which may counter the symptoms and progress of AD.
  • Manabu Murakami, Hidetoshi Niwa, Tetsuya Kushikata, Hiroyuki Watanabe, ...
    2014 Volume 37 Issue 5 Pages 834-839
    Published: May 01, 2014
    Released: May 01, 2014
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    The effects of inhalation anesthesia (2% isoflurane, sevoflurane, or enflurane) and intraperitoneal anesthesia with pentobarbital (65 mg/kg) were compared in rats using an electrocardiogram (ECG) and determination of blood oxygen saturation (SPO2) levels. Following inhalation anesthesia, heart rate (HR) and SPO2 were acceptable while pentobarbital anesthesia decreased HR and SPO2 significantly. This indicates that inhalation anesthesia is more preferable than pentobarbital anesthesia when evaluating cardiovascular factors. Additionally, pentobarbital significantly increased HR variability (HRV), suggesting a regulatory effect of pentobarbital on the autonomic nervous system, and resulted in a decreased response of the baro-reflex system. Propranolol or atropine had limited effects on ECG recording following pentobarbital anesthesia. Taken together, these data suggest that inhalation anesthesia is suitable for conducting hemodynamic analyses in the rat.
  • Xiaowei Duan, Hongxing Xin, Hong Yan
    2014 Volume 37 Issue 5 Pages 840-846
    Published: May 01, 2014
    Released: May 01, 2014
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    The inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has demonstrated potential for the treatment of various components of metabolic syndrome. In this study, a series of 1,4-diaryl-1,4-dihydropyrazines were designed as inhibitors of 11β-HSD1 based on the structure–activity relationship of known 11β-HSD1 inhibitors through docking simulations. The docking simulation results supported the initial pharmacophore hypothesis: the docking results of the known inhibitors with 11β-HSD1 suggested a similar interaction of 1,4-diaryl-1,4-dihydropyrazines with the catalytic site of 11β-HSD1. Twelve of these compounds were synthesized through the cyclization of N,N-dialkylanilines with anilines, and their structures were determined by 1H-NMR, 13C-NMR, high resolution (HR)-MS, and single-crystal X-ray diffraction. The inhibitory activities of these compounds against human 11β-HSD1 were investigated in vitro through a scintillation proximity assay using microsomes containing 11β-HSD1.
  • Naoko Sato-Masumoto, Michiho Ito
    2014 Volume 37 Issue 5 Pages 847-852
    Published: May 01, 2014
    Released: May 01, 2014
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    Studying the biosynthesis of oil compounds in Perilla will help to elucidate regulatory systems for secondary metabolites and reaction mechanisms for natural product synthesis. In this study, two types of alcohol dehydrogenases, isopiperitenol dehydrogenases 1 and 2 (ISPD1 and ISPD2), which are thought to participate the oxidation of isopiperitenol in the biosynthesis of perilla, were isolated from three pure lines of perilla. Both ISPD1 and ISPD2 oxidized isopiperitenol into isopiperitenone with an oxidized form of nicotinamide adenine dinucleotide (NAD+) cofactor. ISPD1 used both isopiperitenol diastereomers, whereas ISPD2 used cis-isomer as a substrate. However, only ISPD2 was isolated from piperitenone-type perilla. These results suggests that in perilla, ISPD2 is related to the biosynthesis of piperitenone, which was formed via (−)-cis-isopiperitenol.
Notes
  • Hiroaki Takahashi, Takeshi Chiba, Tomohiko Tairabune, Yusuke Kimura, G ...
    2014 Volume 37 Issue 5 Pages 853-857
    Published: May 01, 2014
    Released: May 01, 2014
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    It is unknown whether nutritional status influences pain intensity in cancer patients receiving a transdermal fentanyl patch (FP). This study aimed to determine whether nutritional status is associated with pain intensity and to evaluate the influence of changes in nutritional status on pain intensity in cancer patients receiving transdermal FP treatment. We included 92 patients receiving transdermal FP treatment for the first time with switching from oxycodone. The patients were classified into low- and normal-nutrition groups based on their nutritional status, which was assessed according to the Nutrition Risk Screening 2002 (NRS 2002) parameters. The pain intensity of each patient was evaluated by a numeric rating scale (11-point scale from 0 to 10). NRS 2002 score and pain intensity were obtained on day 3 after the FP was applied to the skin. Pain intensities were significantly higher among patients in the low-nutrition group than among patients in the normal-nutrition group. NRS 2002 scores showed a significant positive correlation with the pain intensities. In 52 of 92 patients, who were evaluated using the NRS 2002 score and pain intensity on day 30 after FP application, the changes in NRS 2002 scores were significantly related to changes in pain intensities (odds ratio, 30.0; 95% confidence interval, 4.48–200.97; p=0.0005). These results suggest that an increase in the NRS 2002 score is a risk factor for an increase in pain intensity in cancer patients receiving FP treatment. Malnutrition may lead to poor pain management in cancer patients receiving FP treatment.
  • Qian Ling, Ming Liu, Min-Xia Wu, Ying Xu, Jian Yang, Hui-Hui Huang, Ch ...
    2014 Volume 37 Issue 5 Pages 858-864
    Published: May 01, 2014
    Released: May 01, 2014
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    Diabetic neuropathy is characterized by progressive degeneration of nerve fibers associated with diabetes mellitus. Antidepressants and anticonvulsants are the mainstay of pharmacological treatment, but are often limited in effectiveness against the core clinical feature of pain. In the current study, we examined the potential effects of koumine, a Gelsemium elegans BENTH alkaloid, using a rat model of diabetic neuropathy. Rats were administered intraperitoneally a single dose of streptozocin (60 mg/kg) to induce type 1 diabetes. Koumine was given at a dose range of 0.056–7 mg/kg subcutaneously for one week starting 3 weeks after streptozocin adminstration. Behavioral responses to mechanical stimuli were evaluated every day after streptozocin injection. At 4 weeks after streptozocin injection, sensory nerve conduction velocity (SNCV) and morphological alternation of sciatic nerves were assessed by electron microscopy. Diabetic rats developed mechanical hyperalgesia within 3 weeks after streptozocin injection and exhibited reduced SNCV and impaired myelin/axonal structure. Koumine treatment of diabetic rats decreased neuropathic pain behavior as early as after the first administration. At a dose of 7 mg/kg, koumine was more effective than gabapentin (100 mg/kg), and decreased mechanical sensitivity threshold to a level comparable to healthy control. Repeated treatment of koumine significantly reduced the damage to axon and myelin sheath of the sciatic nerve and increased SNCV, without affecting body weight and blood glucose. These findings encourage the use of koumine in the treatment of diabetic neuropathy.
  • Ayami Sato, Nantiga Virgona, Akira Ando, Masako Ota, Tomohiro Yano
    2014 Volume 37 Issue 5 Pages 865-870
    Published: May 01, 2014
    Released: May 01, 2014
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    Vascular endothelial growth factor (VEGF) plays a crucial role in tumor angiogenesis and represents an attractive anticancer target. We have previously demonstrated that a redox-silent analogue of α-tocotrienol, 6-O-carboxypropyl-α-tocotrienol (T3E) exhibits potent anti-carcinogenic property in human malignant mesothelioma (MM) cells. However, inhibition of tumor growth by targeting VEGF pathway remains undetermined. In this study, we explored the inhibitory effect of T3E on the paracrine secretion of VEGF in MM cells under mimicked hypoxia by cobalt chloride (CoCl2). In this study we examine whether T3E can suppress the secretion of VEGF in MM cells exposed to mimic hypoxia by cobalt chloride (CoCl2). We found that CoCl2-induced hypoxia treatment leads to increased up-regulated hypoxia-inducible factor-2α (HIF-2α) and subsequently induced the secretion of VEGF in MM cells. This up-regulation activation mainly depended on the activation of Yes, a member of the Src family of kinases. Treatment of hypoxic MM cells with T3E effectively inhibited the secretion of VEGF, On the other hand, T3E inhibited CoCl2-induced gene expression of VEGF due to the inactivation of Yes/HIF-2α signaling. These data suggest that Yes/HIF2-α/VEGF could be a promising therapeutic target of T3E in MM cells.
  • Young-Mi Kim, Hee-Sung Chae, Eun Joo Lee, Min Hye Yang, Jin Hee Park, ...
    2014 Volume 37 Issue 5 Pages 871-876
    Published: May 01, 2014
    Released: May 01, 2014
    [Advance publication] Released: February 05, 2014
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    Citrus species has been traditionally used in Korea for the treatment of coughing, sputum and dyspepsia. Of the known citrus flavonoids, 6-demethoxytangeretin was reported to exert anti-inflammatory activity. In order to determine the anti-allergic activity of 6-demethoxytangeretin, we examined whether or not 6-demethoxytangeretin was able to suppress activation of the human mast cell line, HMC-1, induced by phorbol 12-myristate 13-acetate (PMA) plus A23187. Interleukin-6 production and relevant gene expression in activated HMC-1 cells were determined by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis. Also, the involvement of the anaplastic lymphoma kinase (ALK) and mitogen-activated protein kinases (MAPKs) in activated HMC-1 cells were studied. 6-Demethoxytangeretin suppresses interleukin–6 production, tumor necrosis factor-alpha gene expression, ALK and MAPKs in HMC-1 cells stimulated by PMA plus A23187. Therefore, it was evident that 6-demethoxytangeretin suppressed activation of HMC-1 cells by PMA plus A23187 by inhibiting the activity of ALK and MAPKs and subsequently suppressing gene expression, which suggest that 6-demethoxytangeretin may be involved in the regulation of mast cell-mediated inflammatory responses.
  • Mayumi Tamura, Tomoe Watanabe, Takanori Igarashi, Tomoharu Takeuchi, K ...
    2014 Volume 37 Issue 5 Pages 877-882
    Published: May 01, 2014
    Released: May 01, 2014
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    Galectins are a group of animal lectins characterized by their specificity for β-galactosides. In our previous study, we showed that a human galectin-1 (hGal-1) mutant, in which a cysteine residue was introduced at Lys28, forms a covalently cross-linked complex with the model glycoprotein ligands asialofetuin and laminin by using the photoactivatable sulfhydryl reagent benzophenone-4-maleimide (BPM). In the present study, we used several hGal-1 mutants in which single cysteine residues were introduced at different positions and examined their ability to form a covalent complex with asialofetuin or laminin by using BPM. We found that the efficiency of formation of the cross-linked products differed depending on the positions of the cysteine introduced and also on the ligand used for crosslinking. Therefore, by using different cysteine hGal-1 mutants, the chances of isolating different ligands for hGal-1 should increase depending on the systems and cells used.
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